Field of the Invention
This invention relates to bone-seeking radioactive metal-chelant compositions that are suitable for administration to a Patient having: bone pain; one or more calcific tumors; or in need of a bone marrow suppression procedure.
Description of Related Art
Radiopharmaceuticals based on metal-chelant complexes have been used to diagnose and treat bone cancer. For example, Quadramet® (trademark of Lantheus Medical Imaging, Inc.) is a commercially available chelate formed between Sm-153 and ethylene-diaminetetramethylenephosphonic acid (EDTMP) that is currently indicated for the pain associated with bone metastases (U.S. Pat. No. 4,898,724). Typical dosages are 1 mCi of Sm-153 per kg body weight of the patient. Thus for a 70 kg patient the dosage would be 70 mCi.
U.S. Pat. No. 5,059,412 teaches the use of Sm-153, Gd-159, Ho-166, Lu-177 and Yb-175 chelates with chelants derived from the 1,4,7,10-tetraazacyclododecane moiety including 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (DOTMP), while U.S. Pat. No. 5,064,633 teaches the above metals plus Y-90. Compositions of Sm, Gd, Ho, Lu and Y with DOTMP comprising predominately non-radioactive metal with the corresponding radioactive metal (e.g. Sm-152 with Sm-153 at μCi levels) were prepared and biodistribution data in rats was obtained.
A therapeutically effective biodistribution (fate of the activity after administration) for a therapeutic bone agent includes high bone uptake, low soft tissue uptake, rapid clearance of the activity not associated with bone, and high lesion-to-normal bone ratio. Compositions that do not have these characteristics are detrimental to the patient. For example, high soft tissue uptake would result in the patient receiving a high radiation dose to the liver, bone marrow or other soft tissue leading to undesirable side effects.
Radionuclides such as Sm-153 are prepared in a nuclear reactor by bombarding purified targets of the element containing one less neutron and in the process generate radionuclidic impurities. For example, to produce Sm-153 the target that is irradiated is Sm-152. When Sm-153 decays, Eu-153 is formed and an unwanted impurity, radioactive Eu-154 is formed from neutron capture by Eu-153.
The impurities can be detrimental to institutions from both a patient and a waste disposal standpoint. For example, too much Eu-154 administered to a patient would result in the isotope giving an undesirable dose to a patient for a long period of time because of its half-life of 8.8 years. In addition, the dose that is excreted in the urine by the patient containing Eu-154 is a concern and institutions may be forced to collect the radioactive urine. Disposal of the product vials containing residual activity can be a problem. These vials and syringes are typically allowed to decay for 10 half-lives prior to disposal. This is a reasonable amount of time for Sm-153 (about 20 days) but not for Eu-154 (about 88 years). Processes must be implemented in order to deal with waste disposal of vials and syringes that are used. This makes the use of these types of radiopharmaceuticals more complex and institutions may chose not to use the drugs.
In addition, these long-lived impurities cause issues with the radioactive licensing process for the institution. Typically institutions are only allowed small amounts of long-lived radionuclides (having half-lives greater than 120 days) before they are required to have financial assurance. Financial assurance can be very expensive especially for institutions that only handle short-lived isotopes.
The specifications for Quadramet® call for the product to contain less than 0.093 microcuries (μCi) of Eu-154 per millicurie (mCi) of Sm-153 at Expiration Date (http://health.phys.iit.edu/extended_archive/0001/msg00922.html, http://acnp-cal .org/SM1531NS.html) or 4 days from the manufacture date (http://www.ibamolecular.eu/products/quadrainet). This restriction limits the expiration time of the drug. Since Sm-153 decays faster than Eu-154, the longer the Sm-153 solution decays, the higher the amount of Eu-154 in the sample relative to Sm-153. Thus expiration of not only formulated Quadramet® (e.g. Ca-EDTMP + Sm-153) but also the Sm-153 used to produce Quadramet® is limited by the amount of Eu-154 in the sample.
In nuclear reactors such as the one at the University of Missouri in Columbia, Mo., the Sm-152 samples are irradiated for one week in the “flux trap” in order to produce the high specific activity Sm-153 required for the production of Quadramet®. The flux trap is only accessed once a week and therefore high specific activity Sm-153 can only be produced on a weekly basis. Because of the growing amount of Eu-154 compared to Sm-153, the isotope can only be used for a short period of time. Thus the drug is not available to treat patients on some days of the week. The flux trap portion of the reactor is also the most expensive to access (requiring reactor shut-down), thus increasing the production cost of the isotope.
Clearly, there is a need for a product with a longer shelf life and a better impurity profile.